The pulmonary route of administration has been used for many years for the local treatment of lung diseases; many drugs have long been valued for their local effectiveness in such treatment. In recent years, the respiratory tract has become an attractive route of administration for a large range of molecules and drug substances. Since the early 1990s, there has been an intensive growing interest in systemically delivering agents such as biotechnology derived proteins and peptides via the respiratory tract. Examples of these include anti-IgE and insulin, which are difficult to formulate orally. In addition, pulmonary inhalation is also becoming an attractive route of administration for chemotherapeutic agents, such as Doxorubicin and 5-Fluorouracil, to treat bronchogenic carcinomas.
Systemic drug absorption has recently been investigated, e.g. for the treatment of diabetes mellitus and pain treatment (Labiris N. R. & Dolovich M. B. (2003) Pulmonary Drug Delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Journal Clin Pharmacol. 56: 588-99). In addition, major areas of pulmonary research are currently aimed at asthma (Hardy J. G, Chadawick T. S. (2000) Sustained Release Drug Delivery to the lungs. Clin Pharmacokinet. 39:1-4), cystic fibrosis (Garcia-Contreras L, Hickey A J. (2002) Pharmaceutical and biotechnological aerosols for cystic fibrosis therapy. Advanced Drug Delivery reviews. 54: 1491-1504), lung cancer (Rao R., Markovic S. and Anderson P. (2003) Aerosol Therapy for Malignancy Involving the Lungs. Current Cancer Drug Targets. August; 3(4):239-50). and tuberculosis (Pandey R. and Khuller G. K. (2005) Antitubercular inhaled therapy: opportunities, progress and challenges. The Journal of Antimicrobial Chemotherapy. 55 (4): 430-435; Zahoor A, Sharma S, Khuller G K. (2005) Inhalable alginate nanoparticles as antitubecular drug carriers against experimental tuberculosis. International Journal of Antimicrobial Agents. 26: 298-303).
Advantages of the pulmonary route include rapid drug deposition in the target organ, using a lower dose, which results in fewer systemic side effects than other routes of administration. Another advantage of the pulmonary route is that there is no first pass metabolism.
Drug delivery to the lungs requires an aerosol vehicle, which consists of either aerosol droplets containing the drug, or powder particles of an appropriate size for lung delivery (Finlay, W. H. Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction, Academic Press, 2001). The deposition of an aerosol in the lungs depends on its particle size distribution. The most common pulmonary delivery systems can be classified as nebulizers, propellant-metered dose inhaler (pMDI) and dry powder inhaler (DPI). Advances in dry powder inhalation technology and the known advantages of dry powders over solutions have made DPIs a very attractive drug delivery method. However, dry powder delivery to the lungs remains challenging due to powder aggregation which increases the particle size above the optimal particle diameter which in general terms for deep lung deposition is between 1 and 5 μm (Bosquillon C., Lombry C., Preat V. and Vanbever R. (2001) Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerolization performance. Journal of Controlled Release. 70: 329-339; Dailey L. A., et al. (2003) Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features. Journal of Controlled Release. 86: 131-144; Lucas et al. (1999) Lucas et al. (1999) Enhancement of small particles size dry powder aerosol formulations using an ultra low-density additive. Pharmaceutical Research 16-1643-47.
As mentioned above, in order to reach the alveolar region of the lungs particles must have an adequate Mass Median Aerodynamic Diameter (MMAD) ranging from about 1 to 5 μm (Bosquillon, C. et al. (2001), supra). Larger particles are mostly deposited in the tracheo bronchial area while somewhat smaller particles are exhaled. A common technique to manufacture inhalable powders is spray drying. Here the obstacle is that powders produced by this method are more cohesive, leading to an inadequate dispersion during aerolization (Rabbani, N. R., Seville P. C., (2005) The influence of formulation components on the aerolization properties of spray dried powders. J of Controlled Release. 110: 130-140). Different strategies have been proposed in order to solve such problems. One approach is to use the advantages of large and porous aerosols particles (Edwards D. A. et al. (1998) Recent advances in pulmonary drug delivery using large, porous inhaled particles. J Appl Physiol 85: 379-85; Tsapis N, et al. (2002) Trojan particles: Large porous carrier of nanoparticles for drug delivery. Proc. Natl. Acad. Sci. 99: 12001-5). These particles possess low mass density and a larger geometric size. They are characterized by geometric sizes larger than 5 μm and mass densities around 0.1 g/cm3 or less. However, such particles improve the deposition rate in the lungs but they might not influence the drug dissolution. Drug dissolution in the lungs is a prerequisite for drug uptake. Only what is dissolved can be absorbed. Davies and Feddah (2003) had shown that the dissolution rate of poorly soluble drugs is influenced by their aerosol particle size (Davies N. M and Feddah M. R. (2003) A novel method for assessing dissolution of aerosol inhaler products. International Journal of Pharmaceutics. 255:175-87).
Nanomedicine is an emerging field in biomedical sciences. Drug delivery systems involving nanoparticles have been investigated for different routes of administration. Nanoparticles are solid colloidal particles ranging from 10 to 1000 nm. They consist of macromolecular materials and can be used as adjuvants in vaccines, or as a drug carrier, in which the drug is dissolved, entrapped, encapsulated and/or to which the active principle is adsorbed or attached. Nanoparticles may act as a drug vehicle able to target tumor tissues or cells, to a certain extent, while protecting the drug from premature inactivation during the transport (Kreuter, Jorg (1991) Nanoparticle-based dmg delivery systems. Journal of Controlled Release. 16: 169-176).
The first nanoparticle-containing intravenous drug delivery system was recently approved as medicine in the United States under the name Abraxane®. It contains albumin-bound paclitaxel for the treatment of metastatic breast cancer (Abraxane [prescribing information]. Schaumburg, III: Abraxis Oncology, a Division of American Pharmaceutical Partners, Inc; January 2005). Nanoparticles have been proposed for pulmonary administration to utilize their advantages in drug delivery to the lungs (Sham J. O, Zhang Y, Finlay W. H, Roa W. H, Raimar L. (2004) Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. International Journal of Pharmaceutics. 269: 457-67). Furthermore, nanoparticles exhibit certain characteristics that make them ideal for pulmonary drug delivery and for treating lung specific diseases like lung cancer. Research has shown that nanoparticles avoid unwanted mucociliary clearance and in some cases phagocytic clearance (Grenha, Seijo B, Remu{hacek over (n)}án-López C. (2005) Microencapsulated chitosan nanoparticles for lung protein delivery. European Journal of Pharmaceutical Sciences. 25: 427-37) by remaining in the lung lining fluid until dissolution (Schürch S, Geiser M, Lee M M, Gehr P. (1999) Particles at the airway interfaces of the lung, Colloids and surfaces B: Biointerfaces. 15: 339-53) or translocation by the epithelium cells (Oberdörster et al. 2005 An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environmental Health Perspectives. 2005.113; 823-39). One issue with pulmonary nanoparticle delivery is that their small size limits their lung deposition. Aerosolized nanoparticles have only very limited sedimentation, inertial impaction or diffusion, which causes them to be predominantly exhaled from the lungs after inhalation (Finlay et al. (2001), supra; Tsapis et al. (2002), supra; Grenha et al. (2005) supra). However, Sham et al. have shown that nanoparticles can be incorporated into carrier particles to produce the appropriate size for pulmonary drug delivery (Sham et al. (2004), supra).
In light of the foregoing, there is a need for further improvements in inhalable particles for delivery of drugs and other agents.